1. Field of the Invention
The present invention relates to a pharmaceutical composition comprising chalcone or its derivatives having matrix metalloproteinase inhibitory activity.
2. General Background and State of the Art
Chalcones (or chalcone derivatives) are compounds having the basic C6-C3-C6 arrangement in which middle three carbon atoms do not form a closed ring. These are important precursors in the synthesis of pigment in plant. Since they have anti-oxidant effect, they can do protective action from the harmful UV irradiation (Woo W. S.; Methodology of natural product chemistry (Seoul National University Publishing), pp131-137). These compounds are abundant in the plant of the genus Corepsis. Chalcones in natural origin including 2′6′-dihydroxy-4-methoxychalcone, carthamin, and butein are identified from plants such as cinnamon, red pepper and carthamus flower. Dihydrochalcone is contained in certain species of the genus Rosaceae and Rhododendron, and phloridzin is one of the components in apple tree foliage (Hunter, M. D.; Phytochemistry (Oxford) 34, pp1251-1254, 1993). Chalcones are known as inhibitors for glucose transport and growth of various cells including cancer, which enables to apply them in the prevention from aging and/or cancer (Fuhrmann, G. F., Dernedde, S. and Frenking G.; Biochimica Biophysica Acta, 1110, pp105-111, 1992; Kobor, M., et al.; Cancer Lett., 119, pp207-212, 1997; Calliste, C. A., et al.; Anticancer Res., 21, pp3949-3956, 2001).
Matrix metalloproteinases (MMPs), a family of over 20 proteins are endopeptidase, which degrade or proteolyze the components of the extracellular matrix such as collagen, proteoglycan, and gelatin. They are classified into four groups: collagenase, gelatinase, stromelysin, and membrane-type MMP.
Collagenase proteolyzes the triple helix interstitial collagen and gelatin, and it comprises interstitial collagenase (MMP-1), neutrophil collagenase (MMP-8) and collagenase-3 (MMP-13). These three enzymes share more than 50% sequence similarity, having two zinc-binding sites and one or two calcium binding sites in their core domain (Borkakoti et al.; Nature Struct. Biol, 1, pp106-110, 1994; Bode, et al.; EMBO J., 13, pp1263-1269, 1994; Lovejoy et al.; Science, 263, pp375-377, 1994).
Gelatinase can degrade denatured collagen and type IV, V, VII and X collagen. There are two gelatinases, one is 72 kDa gelatinase-A (MMP-2) secreted from fibroblast, and the other is 92 kDa gelatinase B (MMP-9) secreted from mononuclear phagocytes. They specifically act on type IV collagen, the major component of the basement membrane (Murphy, G. et al.; Biochem. J., 258, pp463-472, 1989; Stetler-Stevenson, W. G. et al.; J. Biol. Chem., 264, pp1353-1356, 1989). These enzymes are very important in cancer invasion and metastasis. As compared with MMP-2, MMP-9 comprises additional sequences with unknown functions between the C-terminal and catalytic domain (Wilhelm, S. M. et al.; J. Biol. Chem., 264, pp17213-17221, 1989).
Stromelysins show a broad substrate spectrum and stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), stromelysin-3 (MMP-11), and matrilysin (MMP-7) are classified as stromelysins (Chin, J. R. et al.; J. Biol. Chem., 260, pp12367-12376, 1985; Whitham, S. E. et al.; Biochem. J., 240, pp913-916, 1986).
Metalloelastinase (MMP-12) and membrane-type MMP such as MT1-MMP (MMP-14), MT2-MMP (MMP-15) and MT3-MMP (MMP-16), are also identified as enzymes in the MMP family.
Many enzymes in the MMP family have substrate specificity. The expression of MMP is induced under various physiological circumstances when remodeling of an extracellular matrix is required (Curry, T. E. Jr., Osteen, K. G.; Biol. Reprod., 64, pp1285-1296, 2001; Damjanovske, S., et al.; Ann. NY Acad. Sci., 926, pp180-191, 2000; Ravanti L, Kahari V M; Int. J. Mol Med., 6, pp391-407, 2000).
Increased expression or activation of MMPs is observed in many pathological states, such as atherosclerosis, restenosis, MMP-dependent-osteopathy, inflammation of the central nervous system, Alzheimer's disease, asthma, skin aging, rheumatoid arthritis, osteoarthritis, septic arthritis, osteoporosis, endometriosis, corneal ulcer synechia, bone disease, proteinuria, abdominal aortic aneurysm, regressive cartilage loss, multiple sclerosis, myelinated nerve loss, liver fibrosis, nephroglomerular disease, germinal membrane ruptures, inflammatory bowel disease, gingivitis, periodontal disease, senile macular degeneration, diabetic retinopathy, proliferate vitreous body retinopathy, immature retinopathy, eye inflammation, corneal ulceration, Sjogren's syndrome, myopia, eyes tumors, rejection of cornea implantation, angiogenesis and cancer metastasis. (Woessner Jr.; Ann. NY Acad. Sci., 732, pp11-21, 1994; Warner et al.; Am. J. Pathol, 158, pp2139-44, 2001; Stetler-Stevenson; Surg. Oncol. Clin. N. Am., 10, pp383-92, 2001).
For example, stromelysins are known to be the major enzyme for disruption of cartilage (Murphy, G. et al.; Biochem. J., 248, pp265-268, 1987). Collagenases, gelatinases and stromelysins are responsible for the degradation of the extracellular matrix in many retinopathies (Bruns, F. R. et al.; Invest. Opthalmol. and Visual Sci., 32, pp1569-1575, 1989). Collagenases and stromelysins are identified in fibroblast from gingiva in inflammation and the activity of the enzyme is dependent on the degree of inflammation (Overall, C. M. et al.; J. Periodontal Res., 22, pp81-88, 1987). MMP activity is highly enhanced in response to the bacterial infection and inflammation in gingival crevicular fluid taken from patients with periodontal disease. Destruction of collagen in the periodontal matrix by MMP leads to gingival recession, pocket formation and tooth movement (Goulb, L B., Ryan M. E. Williams R. C.; Dent. Today, 17, pp102-109).
Recent reports have also shown that MMP-1 activity is highly induced in Alzheimer's disease, and MMP-1 and MMP-3 are involved in the pathophysiology of the disease (Leake A, et al.; J. Neurosci. Lett., 291 pp201-3, 2000; Yoshiyama Y, et al.; Acta Neuropathol. (Berl), 99, pp91-5, 2000).
It is also found that MMP-9 is the major MMP in bronchoalveolar lavage fluid and bronchial mucosa in asthma and MMP-2 and MMP-9 are crucial for the induction of bronchial asthma (Mautina et al., J. Allergy Cli.n Immunol., 104, pp530-533, 1999; Kumagai et al., J. Immunol., 162, pp4212-4219, 1999; Bechy Kelly et al., Am J Respir Crit Care Med, 162, pp1157-1161, 2000).
MMPs are also responsible in solar UV radiation-induced skin damage, affecting skin tone and resiliency leading to premature aging. The symptoms of which include leathery texture, wrinkles, mottled pigmentation and laxity. Therefore, MMP inhibitors could be included in cosmetics for anti-photoaging or anti-wrinkle treatment (Hase T et al.; Br. J. Dermatol, 142, pp267-273, 2000; Fisher G J; Photochem. Photobiol., 69, pp154-157, 1999).
Since MMP inhibitors can be applied to the treatment and prevention of many diseases, development of MMP inhibitors as new therapeutics is expected. These inhibitors need to be administered for a long time, so that desirable inhibitors should not have toxic or adverse effect with good patient compliance.